Among men, carcinoma of the prostate is the second most common cancer and the second most common cause of death from cancer in the United States. Each year over 130,000 men are diagnosed with prostate cancer and over 30,000 will die from the disease ((1992) MMWR 41:459). Typically, 61% of all deaths from prostate cancer occur within five years of diagnosis and 88% within ten years (Smart (1997) Cancer 80:1835–1844). Moreover, despite the availability of risk assessment tools, the optimal therapy for treating prostate cancer remains controversial (Small (1998) Drugs Aging 13:71–81). For example, although certain markers of prostate cancer progression such as prostate-specific antigen (PSA) have proven valuable in the diagnosis and management of prostate cancer, as currently used, PSA is insufficiently sensitive and specific for early detection or staging of the malignancy (Daher et al. (1998) Clin. Chem. Lab. Med. 36:671–681).
In addition, in some patients with metastatic disease of the prostate, hormone therapy (e.g., antiandrogen, estrogen, etc.) is frequently used. However, many patients on hormone therapy develop hormone resistance and the management of hormone refractory disease is a major clinical problem (Ismail et al. (1997) Tech. Urol. 3:16–24). The death of patients from prostate cancer is related to the development of clones of cells capable of multiplying and metastasizing without androgen stimulation. To date, efforts to suppress these cells have been of limited success (Newling (1996) Eur. Urol. Suppl. 2:69–74). This is in part due to the fact that the initial events in the development of prostate cancer are not well understood.
Normally, cell numbers in the prostate gland are regulated by androgens through separate pathways that include a) inhibition of cell death (apoptosis), b) induction of cell proliferation (Step-1), and c) inhibition of cell proliferation (Step-2, proliferation shutoff). In normal tissue, the apoptotic and proliferative activities are minimal and apparently, Step-2 (inhibition of cell proliferation) maintains the integrity of the tissue. Prostate cancer cells evolve when this circuitry fails in the initial or early phases in prostate cancer.